Catalytic hydrogenation of the keto group of calcium 5-ketogluconate and product



Patented Aug. 8, i939 CATALYTIC HYDRQGENATION OF THE KETO GROUP OF CALCIUM -KETO- GLUCONATE AND PRODUCT Richard Pastel-hack, Brooklyn, and Ellis V. Brown, Jamaica, N. Y., assignors to Charles Pfizer & Company, Brooklyn, N. Y., a corporation of New Jersey No Drawing. Application July 20, 1938, Serial No. 220,330

3 Claims. (01. 260-535) This invention relates to the catalytic hydro- The hydrogenation product is a mixture of genation of the keto-group of calcium 5-keto-dcalcium-l-idonate and calcium d-gluconate. gluconate. This is the most readily available Owing to the absence of side reactions when the salt of 5-keto-gluconic acid. It may be prereaction temperature has been kept below 65 C.,

5 pared from d-glucose or d-gluconic acid, either the solution of calcium salts resulting from the 5 by nitric acid oxidation (Kiliani, Berichte hydrogenation, after removal of the catalyst by 553:2817-2826, 1922) or by oxidative fermentafiltration, is suificiently pure for pharmaceutical tion (Boutroux, Compt. rend, vol. 102:924, and use. Many efforts have been made to produce a 111:185). therapeutically useful calcium salt mixture of 10 Neither 5-keto-gluconic acid nor its known de high solubility, but with little success. It was 10 rivatives are of great stability, so that it was therefore not to be expected that a natural miximpossible to predict the conditions under which ture of calcium idonate and calcium gluconate it could be hydrogenated without serious decomresulting from the hydrogenation of calcium-5- position. Moreover, the calcium salt is so nearly keto-gluconate would serve the purpose. Howinsoluble in water that it could not have been ever, it was found that this product, an amor- 15 expected to react. phous solid when dry, is so soluble in water It was found experimentally that Ipatieffs that the concentration of its aqueous solutions conditions for the reduction of sugars,heatingthe is limited only by practical considerations such reaction mixture at 130 C. under a pressure of as viscosity.

about 100 atmospheres in the presence of a nickel Example-240 grams of calcium 5-keto-gluco- 20 catalyst, completely destroyed the calcium 5- nate containing three molecules of water of crysketo-gluconate. It is known in the art that mettallization (CeH90'7)2Ca.3H2O are suspended in als of the platinum group usually catalyze hy- 1000 cc. of distilled water and treated with 35 g. drogenation under conditions less severe than of Rainey nickel catalyst. The suspension is 5.; those required for nickel. The calcium 5-ketoplaced in an autoclave and heated at 60 C. with gluconate was therefore subjected to treatment agitation under a hydrogen pressure of 100 atwith hydrogen at room temperature under 100 mospheres. After some 4 hours heating, the abatmospheres pressure and in the presence of a sorption of hydrogen ceases. The pressure is palladium catalyst, but no visible hydrogen abthen released and the solution filtered from the so sorption took place. The temperature was then catalyst, which can be reused without further raised to 100 C. in the course of several hours, treatment. Boiling a sample of the filtrate with but still without result. Fehlings solution shows the absence of reducing We have now found, however, that the nearly substances, indicating complete hydrogenation. insoluble calcium 5-keto-gluconate may be suc- The colorless filtrate is evaporated to dryness cessfully hydrogenated in aqueous suspension in either under vacuum or on a steam bath; or al- 35 the presence of a Rainey nickel catalyst at a ternatively the solid product may be precipitemperature of 25 to 70 C. with a hydrogen tated with alcohol. pressure of some 80 atmospheres or more. In- In either case, the product is an amorphous asmuch as the calcium 5-keto-gluconate and its m xture O Ca l-idonate and Calcium reduction products are neutral substances, the conate. This mixture is not crystallizable. It is 40 nickel catalyst is unaffected and can be used useful in calcium therapy, being IlOrltOXiC and repeatedly. For the same reason corrosion-remore soluble than any previously known calcium sisting equipment is not necessary and reaction prepa t o It is also possible to a e from can be carried out in an ordinary iron autothe mixture substantial amounts of the rare to clave. At pressures below 80 atmospheres, hyl-idonic acid in pure form, for instance by the drogenation is rather slow at the comparatively method used by van Ekenstein and de Bruyn low temperature used, but for the preparation of (Rec. trav. 18:305, 1899). Dibenzal l-idonic acid a pure product temperatures above 65 C. are of melting point 225 C. can be obtained from not advisable because they cause decomposition. the hydrogenated mixture. Hydrolysis of the 5,0 Considerably higher pressures may be used withdibenzal compound by means of dilute sulfuric out harmful effect. At any pressure substantialacid gives a solution of pure l-idonic acid. ly above so atmospheres with an efiicient nickel From 1- 0ni acid Separated f m h prod-' catalyst hydrogenation takes place at a practinot of this invention, we have been able to cal rate at temperatures as low as 40 C., and prepare for the first time two crystalline ido- 5 even proceeds slowly at room temperature. natesnamely sodium idonate and lithium ido- 66 nate, by reacting the acid with a corresponding alkali.

Calcium-l-idonate, (or the mixture of calciuml-iodonate and calciumd-gluconate resulting from our hydrogenation process) exerts a stabilizing effect upon over-saturation solutions of calcium gluconate. For example, if 100 grams of the dried hydrogenation mixture containing calcium idonate are added to an aqueous solution of 50 grams of calcium-d-gluconate in 600 cc. of water, the solution will remain stable. Such a solution obviously contains 20% of calcium aldonates, and since calcium idonate is an isomer of calcium gluconate the available calcium content is equivalent to that of a 20% solution of calcium gluconate.

More highly concentrated solutions of calcium gluconate may be stabilized by the addition of a larger proportion of calcium idonate, Whether added as such or as a constituent of our hydrogenation product.

The invention claimed is:

1. As a new composition of matter, a mixture of calcium l-idonate and calcium d-gluconate, soluble in any practical proportion of water.

2. As a new composition of matter, a mixture of calcium l-idonate and calcium d-gluconate, obtained by the hydrogenation of calcium 5-ketogluconate, amorphous when dry, and soluble in any practical proportion of water.

3. Process for producting a mixture of calcium d-gluconate and calcium l-idonate by hydrogenation of calcium 5-keto-gluconate in aqueous suspension under a pressure of above 80 atmospheres in the presence of a nickel catalyst at a temperature between 25 and 70 C.

RICHARD PAS'IERNACK. ELLIS V. BROWN. 

